List of recommendations

1. There are multiple causes of cholangiopathy. We recommend that cholestatic liver biochemistry with typical cholangiographic features in the absence of other identifiable causes of secondary sclerosing cholangitis is usually sufficient for a diagnosis of PSC (strength of recommendation: STRONG; quality of evidence: MODERATE).

2. We recommend that MRCP should be the principal imaging modality for the investigation of suspected PSC. ERCP should be reserved for patients with biliary strictures requiring tissue acquisition (eg, cytological brushings) or where therapeutic intervention is indicated (strength of recommendation: STRONG; quality of evidence: HIGH).

3. We recommend that liver biopsy is normally reserved for possible small duct PSC, assessment of suspected possible overlap variants or instances where the diagnosis is unclear (strength of recommendation: STRONG; quality of evidence: MODERATE).

4. We recommend risk stratification based on non-invasive assessment. Clinical scores are an emerging theme but no single method can be recommended at present to predict individual patient prognosis. Given the unpredictable disease course and the serious nature of the complications of PSC, patients should receive lifelong follow-up (strength of recommendation: STRONG; quality of evidence: VERY LOW).

5. We recommend that ursodeoxycholic acid (UDCA) is not used for the routine treatment of newly diagnosed PSC (strength of recommendation: STRONG; quality of evidence: GOOD). For patients already established on UDCA therapy, there may be evidence of harm in patients taking high dose UDCA 28–30 mg/kg/day (strength of recommendation: WEAK; quality of evidence: LOW).

6. We recommend that UDCA is not used for the prevention of colorectal cancer or cholangiocarcinoma (strength of recommendation: STRONG; quality of evidence: HIGH).

7. We recommend that corticosteroids and immunosuppressants are not indicated for the treatment of classic PSC (strength of recommendation: STRONG; quality of evidence: HIGH). In those patients with additional features of autoimmune hepatitis (AIH) or IgG4-related sclerosing cholangitis (IgG4-SC), corticosteroids may be indicated (strength of recommendation: STRONG; quality of evidence: MODERATE).

8. We recommend that endoscopic screening for oesophageal varices should be done in line with international guidelines where there is evidence of cirrhosis and/or portal hypertension (strength of recommendation: STRONG; quality of evidence: HIGH).

9. We recommend that colitis should be sought in all patients with PSC using colonoscopy and colonic biopsies (strength of recommendation: STRONG; quality of evidence: MODERATE).

10. We recommend that patients with suspected PSC undergoing ERCP should receive prophylactic antibiotics (strength of recommendation: STRONG; quality of evidence: MODERATE).

11. We recommend that non-invasive investigations such as MRCP, dynamic liver MRI and/or contrast CT should be performed in patients who have new or changing symptoms or evolving abnormalities in laboratory investigations (strength of recommendation: STRONG; quality of evidence: MODERATE).

12. We recommend that patients with PSC should ordinarily not undergo ERCP until there has been expert multidisciplinary assessment to justify endoscopic intervention (strength of recommendation: STRONG; quality of evidence: MODERATE).

13. We recommend that in patients undergoing ERCP for dominant strictures, pathological sampling of suspicious strictures is mandatory (strength of recommendation: STRONG; quality of evidence: STRONG).

14. We recommend that in patients undergoing ERCP for dominant strictures, biliary dilatation is preferred to the insertion of biliary stents (strength of recommendation: STRONG; quality of evidence: MODERATE).

15. We suggest that provision of care should involve a partnership between patients, primary care and hospital-led specialty medicine with consideration made with regard to patient risk assessment, symptom burden and how local services are configured (strength of recommendation: WEAK; quality of evidence: LOW).

16. We recommend that patients with symptomatic, evolving or complex disease should be referred for expert multidisciplinary assessment. Patients with early, stable disease can be managed in general clinics (strength of recommendation: STRONG; quality of evidence: LOW).

17. We suggest that patients with PSC meeting inclusion criteria should be offered referral to a centre participating in clinical trials (strength of recommendation: WEAK; quality of evidence: LOW).

18. PSC is a well-recognised indication for liver transplantation. We recommend that eligibility and referral should be assessed in line with the national guidelines (strength of recommendation: STRONG; quality of evidence: HIGH).

19. We recommend that all patients with PSC should have a risk assessment for osteoporosis. Once osteoporosis is detected, treatment and follow-up should be in accordance with national guidelines (strength of recommendation: STRONG; quality of evidence: MODERATE).

20. Poor nutrition and fat-soluble vitamin deficiency are relatively common in advanced PSC and we suggest that clinicians should have a low threshold for empirical replacement (strength of recommendation: WEAK; quality of evidence: MODERATE).

21. We recommend that in patients with fatigue, alternative causes should be actively sought and treated (strength of recommendation: STRONG; quality of evidence: LOW).

22. We suggest that cholestyramine (or similar) is first-line medical treatment for pruritus. Rifampicin and naltrexone are second-line treatments (strength of recommendation: WEAK; quality of evidence: LOW).

23. We suggest that an elevated CA19.9 may support a diagnosis of suspected cholangiocarcinoma but has a low diagnostic accuracy. Routine measurement of serum CA19.9 is not recommended for surveillance for cholangiocarcinoma in PSC (strength of recommendation: WEAK; quality of evidence: MODERATE).

24. We recommend that when a diagnosis of cholangiocarcinoma is clinically suspected, referral for specialist multidisciplinary meeting (MDM) review is essential (strength of recommendation: STRONG; quality of evidence: MODERATE).

25. We recommend that where cholangiocarcinoma is suspected, contrast-enhanced, cross-sectional imaging remains the initial preferred investigation for diagnosis and staging (strength of recommendation: STRONG; quality of evidence: HIGH). Confirmatory diagnosis relies on histology with the approach to tissue sampling guided by MDM review. Options include ERCP-guided biliary brush cytology/fluorescence in situ hybridisation (FISH)/endobiliary biopsy/cholangioscopy/endoscopic ultrasound (EUS)-guided biopsy and/or percutaneous biopsy (strength of recommendation: STRONG; quality of evidence: HIGH).

26. We suggest that an annual ultrasound scan of the gallbladder should be performed in patients with PSC. If polyps are identified, treatment should be directed by specialist hepatopancreaticobiliary (HPB) MDM (strength of recommendation: WEAK; quality of evidence: LOW).

27. We recommend that patients with PSC who have coexistent colonic inflammatory bowel disease (IBD) should have annual colonoscopic surveillance from the time of diagnosis of colitis in line with the British Society of Gastroenterology (BSG) guidelines (strength of recommendation: STRONG; quality of evidence: HIGH). We suggest that those without IBD may benefit from less frequent 5-year colonoscopy or earlier in the advent of new symptoms (strength of recommendation: WEAK; quality of evidence: VERY LOW).

28. We suggest that in the presence of cirrhosis, hepatocellular carcinoma surveillance should be carried out in accordance with international guidelines (strength of recommendation: WEAK; quality of evidence: LOW).

29. We recommend that because pregnancy in cirrhotic patients carries a higher risk of maternal and fetal complications, patients should have preconception counselling and specialist monitoring (strength of recommendation: STRONG; quality of evidence: LOW).

30. We recommend that patients with PSC should be encouraged to participate in patient support groups (strength of recommendation: STRONG; quality of evidence: VERY LOW).

IgG4-related sclerosing cholangitis (IgG4-SC)

1. We recommend that elevated serum IgG4 levels support the diagnosis of clinically suspected IgG4-related disease (IgG4-RD) but cannot be relied on for making a definite diagnosis, or distinguishing IgG4-SC from PSC (strength of recommendation: STRONG; quality of evidence: MODERATE).

2. We recommend that in patients with suspected IgG4-SC, attempts should be made to obtain a confirmatory histological diagnosis (strength of recommendation: STRONG; quality of evidence: MODERATE).

3. We recommend that other organ involvement (in particular, pancreatic manifestations of IgG4-RD) may provide important information to distinguish IgG4-SC from PSC (strength of recommendation: STRONG; quality of evidence: MODERATE).

4. We recommend that IgG4-SC should be diagnosed according to the recommendations of the international consensus guidelines (strength of recommendation: STRONG; quality of evidence: MODERATE).

5. We recommend that patients with active IgG4–SC should be given corticosteroids as first-line treatment (strength of recommendation: STRONG; quality of evidence: MODERATE).

6. We recommend that all patients with IgG4-SC, including those with multiorgan involvement in IgG4-RD, should be considered for continued immunosuppressive therapy (strength of recommendation: STRONG; quality of evidence: MODERATE).

7. We recommend that patients with complex IgG4-SC and those with suspected malignancy should be referred to a specialist MDM for review (strength of recommendation: STRONG; quality of evidence: LOW).

Definitions

PSC is an immune-mediated chronic liver disease characterised by inflammation, fibrosis and destruction of intrahepatic and/or extrahepatic bile ducts leading to cholestasis, bile duct strictures and hepatic fibrosis, which in turn may progress to cirrhosis, portal hypertension and hepatic decompensation.5 6 A variant known as small duct PSC is characterised by typical cholestatic liver biochemistry and histological findings typical of PSC but with normal appearance of the bile ducts at cholangiography.7 PSC overlap/variant syndromes are conditions with diagnostic features of both PSC and other immune-mediated liver diseases, including autoimmune hepatitis (AIH). These guidelines refer specifically to PSC and its overlap syndromes, and include discussion of IgG4-related sclerosing cholangitis, which can mimic PSC. Causes of secondary sclerosing cholangitis related to other identifiable causes of biliary obstruction leading to injury of the bile ducts are listed in box 1 but are not considered further.

Epidemiology

Population-based studies estimate the incidence of PSC to be 0.91 to 1.3 per 100 000 person-years and may be increasing.8–12 The incidence of small duct PSC is reported to be 0.15 per 100 000 person-years.9 These studies were undertaken in populations of northern European descent in whom the incidence is thought to be highest. The incidence in most other ethnic groups is less clear.

Aetiology

PSC is a progressive biliary disorder strongly associated with inflammatory bowel disease (IBD). The genetic associations with disease risk, presence of chronic inflammation in the portal tracts and the strong association with IBD suggest that PSC is an immune-mediated disease, in which the biliary epithelial cell is a key cell targeted. However, no reliable autoantibodies have been identified and there is no significant response to immunosuppression. To date, genome-wide studies have uncovered susceptibility loci for PSC-IBD, the majority of which have been previously reported as risk factors in other immune-mediated disorders. The strongest association resides within the human leucocyte antigen complex and suggests that disease-specific antigens drive pathogenic immune responses. Genetic determinants account for <10% of total disease liability in PSC-IBD, clearly emphasising the predominant role of environmental factors on ultimate disease susceptibility.

Modes of presentation

Symptoms are rare in early disease. In more established cases, symptoms such as right upper quadrant pain, pruritus, fatigue, jaundice, fever and weight loss are present in 47–56% of patients.11 15 Patients usually present in one of several ways: (i) no symptoms or signs but with an incidental finding of abnormal liver biochemistry, (ii) biochemical screening of patients with newly diagnosed or pre-existing IBD, (iii) jaundice and pruritus secondary to cholestasis, (iv) cholangitis, (v) jaundice secondary to liver failure, (vi) variceal bleeding and/or ascites from portal hypertension or (vii) cholangiocarcinoma (CCA).

Blood tests

Serum liver biochemistry tests are abnormal in approximately 75% of patients with PSC.1 The most common pattern is of a cholestatic picture with raised alkaline phosphatase (ALP) and γ-glutamyl transpeptidase. An elevated serum bilirubin is reported to be present in 28–40% and is a marker of poor prognosis,15–17 but this is likely to be an overestimate with more advanced cases reported by published series. An elevated ALP is a sensitive marker for diagnosis but is not specific. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are often mildly raised and do not necessarily suggest additional features of autoimmune hepatitis. As with other causes of liver disease, a raised AST>ALT may be an indicator of cirrhosis and poor prognosis.18 Other indicators of cirrhosis or portal hypertension include an elevated prothrombin time or international normalised ratio, low albumin and low platelets. There are no autoantibodies diagnostic of PSC. Serum perinuclear antinuclear cytoplasmic antibody is positive in 33–88% of those with PSC but is not specific and is not related to disease activity or prognosis.15 19–22

Similar to clinical outcomes in primary biliary cholangitis (PBC), recent data from retrospective studies support the use of falling ALP (normalisation or <1.5 x upper limit of normal (ULN)) as a stratifier for improved outcome in patients with PSC, independent of the therapeutic modality used23–25

There are contradictory data on whether a raised serum IgG4 in patients with PSC (IgG4 + PSC) correlates with the disease course of PSC. In the study by Mendes,26 IgG4 + PSC was associated with more aggressive disease and progression to transplantation, but this was not seen in a European cohort of 345 patients with PSC.27 A further study including histological assessment of IgG4 staining in 98 liver explants from patients with a diagnosis of PSC, reported raised serum IgG4 levels in 22%, and raised tissue IgG4 levels in 23%.28 Again, those patients with raised IgG4 had a more rapid progression and need for liver transplantation. It is uncertain whether these findings are explained by misdiagnosis in some cases (ie, cases of IgG4-SC incorrectly diagnosed as PSC), or whether they represent a more aggressive phenotype of PSC in those with elevated IgG4 levels. A further assessment of liver explants from patients with PSC undergoing transplantation reported at least moderate IgG4 immunostaining in 24.6% and was associated with higher rates of dominant strictures, although this did not appear to correlate with age or speed of progression of disease.29

Some causes of secondary sclerosing cholangitis may respond well to medical treatment and it is therefore important to exclude secondary causes before making a diagnosis of PSC. Measurement of other biochemical tests, including antinuclear antibodies (ANA), antimitochondrial antibodies (AMA), smooth muscle antibodies (SMA), HIV antibodies, serum angiotensin converting enzyme, total immunoglobulins and immunoglobulin subsets (including IgG4), should be performed and positive results should raise the suspicion of alternative diagnoses or overlap/variant syndromes.

Recommendation 1: There are multiple causes of cholangiopathy. We recommend that cholestatic liver biochemistry with typical cholangiographic features in the absence of other identifiable causes of secondary sclerosing cholangitis is usually sufficient for a diagnosis of PSC (strength of recommendation: STRONG; quality of evidence: MODERATE).

Imaging

Transabdominal ultrasound scanning is rarely useful in the diagnosis of PSC, but may be helpful in excluding other causes of biliary obstruction such as choledocholithiasis, which can complicate stricturing disease and cholestasis in PSC. Ultrasound is also useful in the detection and surveillance of gallbladder polyps and in identifying developing portal hypertension. Contrast-enhanced CT may demonstrate features of cholangiopathy but is used primarily for the diagnosis and staging of suspected CCA.

Endoscopic retrograde cholangiopancreatography (ERCP) has been conventionally regarded as the ’gold standard' for the diagnosis of PSC, where the presence of a typical beading appearance caused by short multifocal strictures of the bile ducts is considered the best supportive evidence for the diagnosis of PSC. However, the risks involved with ERCP and improvement in image acquisition led to magnetic resonance cholangiopancreatography (MRCP) becoming the preferred imaging modality for the diagnosis of PSC. A number of studies have reported that the diagnostic accuracy of MRCP is comparable to that of ERCP, with a sensitivity and specificity of 80–100% and 89–100%, respectively.30–36 A meta-analysis of the diagnostic utility of MRCP included six well-controlled prospective studies and reported a sensitivity and specificity of 86% and 94%, respectively, for the diagnosis of PSC.37 However, MRCP may be less sensitive than ERCP in detecting early changes of PSC and has less specificity in patients with cirrhosis.30 Contrast- enhanced MRI scanning may also provide additional information about liver parenchyma, presence of varices, CCA and lymphadenopathy.

Many of the studies describing and differentiating PSC from other diseases were done before the widespread recognition of IgG4-SC, which may be present in 20–88% of patients with IgG4-RD.38 Whereas some cholangiographic features, such as long biliary strictures with prestenotic dilatations, and low common bile duct strictures, are more suggestive of IgG4-SC, beading, peripheral duct pruning and pseudodiverticula point more towards PSC.39 Cholangiography alone is insufficient to distinguish IgG4-SC, PSC and CCA.40

Recommendation 2: We recommend that MRCP should be the principal imaging modality for the investigation of suspected PSC. ERCP should be reserved for patients with biliary strictures requiring tissue acquisition (eg, cytological brushings) or where therapeutic intervention is indicated (strength of recommendation: STRONG; quality of evidence: HIGH).

PSC with additional features of AIH

There is a reported 1.4–17% overlap of AIH in adults diagnosed with PSC.48–50 Conversely, a prospective study of MRCP and liver biopsy in 59 patients with AIH demonstrated features of PSC in 1.7%.51 These patients typically have cholangiographic features of PSC in combination with findings suggestive of AIH, including younger age, higher transaminases, elevated immunoglobulins, positive ANA, SMA and/or liver/kidney microsomal antibodies and mixed histopathological changes with interface hepatitis as well as the typical biliary pathology of PSC.

Patients who fulfil the diagnostic criteria of AIH published by the International Autoimmune Hepatitis Group respond to treatment with steroids and have a better prognosis than classic PSC, but worse than non-overlap AIH.48 52 An AIH/PSC overlap syndrome is more common in children (where it may be labelled autoimmune sclerosing cholangitis (ASC)), with cholangiographic features of sclerosing cholangitis reported in up to 49% of children with antibody-positive AIH.53 We recommend management of PSC with additional features of AIH according to the EASL guidelines on the management of AIH.54 The importance of identifying an AIH overlap syndrome is due to the potential therapeutic benefit of immunosuppression, and hence liver biopsy is recommended for those with significantly raised transaminases, immunoglobulins or positive AIH autoantibodies (ALT >5 x upper limit of normal (ULN), IgG >x2 ULN, positive ANA, SMA and/or liver/kidney microsomal antibodies).54 Some patients with features of AIH overlap syndrome progress to a more typical PSC phenotype.55 In this situation, ongoing treatment with immune suppression may not be effective and patients may require repeat assessment with cholangiography and consideration of repeat biopsy.

Other overlap syndromes

A PSC/PBC overlap syndrome has been reported in only small case series.56 57 This may reflect the diagnostic difficulty in those with small duct PSC where the classic cholangiographic features are absent and liver biopsy is often not diagnostic. AMAs are positive in <5% of cases of PSC.58

It is not clear whether IgG4-SC can be an overlap syndrome or if it represents a separate condition with similar clinical features. However, a subset of patients with a diagnosis of PSC do have elevated serum levels of IgG4 as discussed elsewhere in the guidelines26 59

What other conditions may be associated with PSC

PSC in inflammatory bowel disease

Abnormal liver biochemistry is common in patients with IBD. In a cohort of 544 patients with IBD, 29% had at least one abnormal liver biochemical test, but only 5.8% had a clinical diagnosis of chronic liver disease (biopsy was not required for diagnosis in this series). When performed in a subset with a suspicion of biliary disease, cholangiographic features of PSC were present in 4.6% of all patients.60 In a recent study, 7.5% of patients with longstanding IBD (over 20 years' duration) with normal liver biochemistry, had evidence of cholangiopathy (9% of Crohn’s disease, 6.8% ulcerative colitis), indicating that PSC may be underdiagnosed within cohorts of patients with IBD.61

IBD is present in 62–83% of patients with PSC of Northern European descent, but rates are as low as 21% elsewhere in the world.8 11 16 62–65 Patients often have extensive colitis, which may be of ulcerative colitis or Crohn’s colitis type. Rectal sparing and backwash ileitis are more common in IBD associated with PSC.66 PSC may be diagnosed before IBD but generally IBD is diagnosed some years before the identification of PSC. Despite potential mechanisms linking active colonic inflammation with the aetiology and activity of PSC, this has never been properly demonstrated. Clinically, the activity of IBD can follow an unpredictable course. Patients with PSC and IBD often describe minimal symptoms even in the presence of endoscopically and biopsy proven active IBD. Treatment of active colitis appears to have no impact on the progression of PSC.67 Case series also show that patients can develop changes of PSC years after colectomy for ulcerative colitis. A number of small case series have described the pattern of IBD in PSC with and without liver transplantation and/or immunosuppression, demonstrating some cases of de novo presentation of IBD after transplantation or a paradoxical worsening of disease activity after liver transplantation despite immunosuppression.68–70 Conversely, other transplant series report a milder course of IBD in those with more progressive PSC and/or improved IBD activity with immunosuppression after liver transplantation.71 72 The reasons for these variable reports and patterns of disease are unknown but suggest that there is at most a weak correlation between activity of PSC and IBD. IBD appears to be rare in IgG4-SC, providing additional means to help distinguish this from IgG4 + PSC.

Other associated conditions

PSC may rarely be associated with some other immune-mediated diseases, including coeliac disease, thyroid disease, Sjögren’s syndrome, type 1 diabetes mellitus, systemic sclerosis, retroperitoneal fibrosis, autoimmune haemolytic anaemia, sarcoidosis and rheumatoid arthritis. An association with these conditions is uncommon and some may relate to IgG4-RD misdiagnosed as PSC (eg, when associated with retroperitoneal fibrosis).

What is the natural history of PSC?

The natural history of PSC is variable and often unpredictable. Most patients are diagnosed in the fourth or fifth decades of life. The mean age of diagnosis is between 32 and 41 years.11 15 73 PSC is uncommon in childhood. Men are affected more commonly, with a male to female ratio of 2:1.

The mean time from diagnosis to death or liver transplantation is 10–22 years.8 12 15 73 74 It should be noted that most published data come from tertiary referral units and probably overestimate the risk of complications and death. A population-based assessment of natural history in Holland demonstrated improved prognosis in the overall PSC population compared with those in liver transplant centres, with a median time from diagnosis to death or transplantation of 21 years and 13 years, respectively.12 Asymptomatic patients are reported to have a better prognosis, but this is probably due in part to lead time bias with diagnosis at an early disease stage. Historically and before liver transplantation, most patients died of complications of cirrhosis. In more recent series, most deaths are due to CCA (58%), liver failure (30%) and variceal bleeding (9%).15 Patients with small duct PSC appear to have a better prognosis and a very low risk of developing CCA, but a significant minority (23%) will develop cholangiographic features of classic PSC over time.75 76 Large retrospective series suggest that patients with PSC and Crohn’s disease have a better prognosis than those with ulcerative colitis.77

These studies have been reinforced by the recent International PSC Study Group (IPSCSG) cohort study of 7121 patients, of whom 2616 progressed to liver transplantation or death (median 14.5 years); and 721 developed hepato-pancreato-biliary malignancy, mainly CCA (n=594) (incidence rate: 5.4 and 1.4 per 100 patient-years, respectively). Of these patients, 65.5% were men, 89.8% had classic/large duct disease and 70.0% IBD.78

Prognostic scoring systems

It is difficult to predict the rate of progression or outcome for individual patients with PSC. Asymptomatic patients are likely to have a better prognosis than those with symptoms. Multivariate analyses in a number of series demonstrate clinically predictable parameters as being markers of poor prognosis. Some groups have devised prognostic models (summarised in table 1) using a variety of parameters, including age, blood results, liver biopsy staging, cholangiographic findings and complications such as a history of variceal bleeding.15–17 74 The most widely used is the revised Mayo natural history model for PSC. As with other models it has a complex formula reflecting the variability and complexity of the natural history of PSC. These models probably have little role for ordinary patient care and are rarely used in clinical practice in the UK. Their main roles are to assist in the timing of liver transplantation and for research studies. Model for End Stage Liver Disease (MELD) and UK Model for End Stage Liver Disease (UKELD) scores may be applied to patients with PSC as for patients with other causes of liver disease, but both may fluctuate highly and overestimate the stage of liver disease in view of the impact of biliary obstruction on the bilirubin component of the scores. The Child-Pugh score has been applied specifically to PSC, with 7-year survival rates of 90%, 68% and 25% for scores A, B and C, respectively.79 Prognostic models using clinical and laboratory parameters for established PSC do not vary widely from data using the simple Child-Pugh score.

Recommendation 4: We recommend risk stratification based on non-invasive assessment. Clinical scores are an emerging theme but no single method can be recommended at present to predict individual patient prognosis. Given the unpredictable disease course and the serious nature of the complications of PSC, patients should receive lifelong follow-up (strength of recommendation: STRONG; quality of evidence: VERY LOW)

Sclerosing cholangitis in children

Raised ALP is normal in growing children and adolescents, and is unreliable for screening for PSC. Abnormal liver biochemistry in children with IBD is common but most is thought not to be related to PSC. In a cohort of 300 children with IBD, sclerosing cholangitis was reported in 6%, with a persistently raised γ-glutamyl transpeptidase being the most predictive marker.80 The proportion of children with abnormal liver biochemistry who develop features suggestive of PSC is not well reported. A prospective study of 55 consecutive children presenting with abnormal liver biochemistry and positive autoantibodies suggests that the distinction between classical PSC and AIH is much less clear in the paediatric population.53 Half of these children with AIH also had changes of sclerosing cholangitis at cholangiography. Most had features of an overlap syndrome with positive autoantibodies, elevated transaminases, elevated immunoglobulins and mixed histological findings of interface hepatitis and portal inflammation. The disease tends to progress to a more classic PSC pattern and become resistant to immunosuppressive treatment in the adult years. Classic PSC has also been described in children but appears to be rare. Some have therefore suggested that PSC is a ‘sequential syndrome’ or long-term consequence of damage from childhood AIH.81 The term autoimmune sclerosing cholangitis (ASC) has been used in children, but whether this is an early phase and/or the same condition as adult PSC remains unclear. MRCP is recommended in children with AIH that responds poorly to medical treatment in order to screen for changes of sclerosing cholangitis.

Children often require liver transplantation at a young age and have a high rate of disease recurrence in the graft.82 Children with classic PSC have a disease pattern mirroring that of adults with a poor response to treatment and a median survival before developing significant events or transplantation of 10–12 years.83 84 The outcome of classic PSC in children is worse than for children with steroid-responsive AIH or ASC, resulting in shorter transplant-free survival (78% at 5 years compared with 87–90% for AIH/ASC).85

Adolescents with PSC should, where possible, be managed in transition clinics before long-term management in adult clinics.

Drug therapies

Dominant bile duct strictures

It is important that in patients presenting with signs of biliary obstruction and/or those who develop changing symptoms or evolving abnormalities in laboratory investigations, non-invasive investigations such as MRCP, dynamic liver MRI and/or contrast CT should be performed and reviewed by a hepatopancreaticobiliary (HPB) MDT before any high-risk invasive endoscopic interventions.

A dominant stricture is often not simple to define in clinical practice but a pragmatic definition is of functional stenoses of the major bile ducts with signs of biliary obstruction shown by worsening liver biochemistry and/or proximal biliary dilatation or symptoms of cholestasis. The prevalence of dominant bile duct strictures in PSC is 36–50%.15 121 124 125 Patients with dominant strictures have significantly worse outcomes than those without, even when regular endoscopic treatment of stenoses is applied and CCA is excluded.125

Decision-making about intervention for dominant strictures is important but complex. A common consensus has been that patients with PSC who do not have significant jaundice and/or have not had episodes of cholangitis in the presence of assumed functionally significant extrahepatic strictures should avoid ERCP unless a clinical suspicion of CCA based on non-invasive imaging is high.

Differentiating benign from malignant causes of dominant strictures is crucial but difficult. Biliary brush cytology is the standard investigation for suspicious biliary strictures but despite excellent specificity, its sensitivity is poor. A systematic review of the published literature (n=747) on the use of biliary brushings in the diagnosis of CCA in PSC reported a sensitivity of 43% and specificity of 97%.126 The sensitivity of cytology from bile aspirates is lower. A single-centre prospective study of systematic biliary brushings at index ERCP in 261 patients with PSC reported malignancy or dysplasia suspicious for malignancy in 7%.127 Additional cases of biliary dysplasia were identified in explants of patients who underwent transplantation. Some international centres use dysplasia in brushings as a marker of in situ carcinoma and refer these patients for consideration for liver transplantation.127 128 However, CCA remains a contraindication to liver transplantation in the UK. Other markers using fluorescence in situ hybridisation (FISH) analysis in biliary brushings or KRAS and p53 in bile have been evaluated, but are not sufficiently sensitive or specific to be useful as screening or diagnostic tests.129–132 A meta-analysis of 828 patients with PSC undergoing assessment by FISH demonstrated sensitivity and specificity of 68% and 70%, respectively.133 Other approaches such as using a panel of biomarkers may show more promise in the future.

Another approach to tissue diagnosis at ERCP is fluoroscopically guided intraductal biopsy without direct cholangioscopy. Selected studies (not PSC specific) demonstrate relatively high rates of tissue confirmation of malignancy (70%) using larger biopsy forceps.134 Rates for confirmatory tissue diagnosis can be improved by multimodal sampling using brushings, biopsy and EUS.135 Similarly, the use of multiple crushed biopsy specimens analysed immediately by a pathologist during the ERCP procedure may improve diagnosis rates.136

Intraductal cholangioscopy can aid the diagnosis of indeterminate biliary strictures. Early case series, including patients with PSC, suggested that very high sensitivities (92–100%) could be achieved for the diagnosis of malignant biliary strictures using direct visualisation without biopsy, although with a decline in specificity to 87–93%.137 138 Larger, more recent studies using video cholangioscopy and multicentre registries have reported high sensitivities (62–99%) and specificities (64–100%) for the diagnosis of biliary strictures.139–143 A UK multicentre experience of cholangioscopy for the diagnosis of CCA in PSC and IgG4- related cholangitis suggests that in comparison with investigation of possible CCA in patients without cholangiopathy, it is similarly efficacious (sensitivity 50%).144 Technological developments and the wider availability of cholangioscopy will probably lead to an increasing role for this procedure in the assessment of strictures in PSC.145 Early studies on the addition of adjunctive techniques to EUS and cholangioscopy, such as intraductal chromoendoscopy, narrow band imaging and confocal laser microscopy, are emerging.139 146–148 These techniques are limited to specialist centres, but availability is expanding.

Endotherapy of dominant bile duct strictures

The exact role of endoscopic therapy in the management of dominant strictures in PSC remains incompletely understood. Investigations in animals and humans suggest that decompression of biliary obstruction prevents further damage and can reverse fibrotic liver disease.149 This is supported by data demonstrating that patients with PSC who achieve normalisation or near normalisation of ALP have improved outcomes compared with those who do not.24 25 It is clear that endoscopic treatment of biliary strictures often improves liver biochemistry and pruritus, and may reduce the risk of recurrent cholangitis. Consensus has been for repeated endoscopic intervention (usually stricture dilatation ± stenting) of dominant biliary strictures in those with symptomatic disease.150–152 Evidence from studies comparing jaundice, cholangitis, transplantation and actuarial survival rates with figures from prognostic models, tend to suggest a benefit of endoscopic intervention for dominant biliary strictures.124 153–155 In contrast, a Swedish study comparing liver biochemistry in those with and without dominant strictures suggested that variations in cholestasis and jaundice are a feature of PSC liver disease and are not a direct consequence of endotherapy of dominant strictures.121

The optimum method and frequency of dilatation of dominant strictures is unclear. Plastic stent insertion with or without prior stricture dilatation has been commonly used. The difficulty with this approach is that further ERCPs are required to remove or replace the stent and there is a high rate of stent occlusion and/or cholangitis within 3 months of insertion. One uncontrolled study of short-term stenting (mean 9 days) reported improved outcome, particularly for resolution of jaundice and symptoms of cholestasis (81% compared with 57% in historical controls undergoing 2–3 monthly elective stent changes).155 Other studies have compared the role of stenting with balloon dilatation, with similar efficacy and lower rates of complications such as cholangitis associated with balloon dilatation alone (18% vs 50%).156 Multiple dilatations are usually required over months or years in order to maintain patency once dominant strictures are identified. A large (n=171) uncontrolled prospective study of patients with PSC included 96 patients with dominant strictures undergoing regular balloon dilatations over a median follow-up of 7 years.157 Over 500 dilatations were performed (only five stents inserted) with low complication rates of 2.2% for pancreatitis, 1.4% for cholangitis and 0.2% for bile duct perforation, and 5- and 10-year transplant free survival rates of 81% and 52%, respectively.

Balloon dilatation in preference to stenting has been advised in European and American guidelines on the management of patients with PSC.1 2 4 Some strictures do not open satisfactorily with balloon dilatation alone and stent insertion is usually recommended in these cases. A meta-analysis in other benign causes of biliary stricture and/or obstruction, shows that insertion of multiple plastic stents offers higher rates of relief of cholestasis (94% vs 60%) and lower complication (mostly cholangitis) rates (20% vs 36%) than single stent insertion.158 In a multicentre randomised trial of patients with PSC and a dominant stricture (n=65), short-term stents were not superior to balloon dilatation and were associated with significantly higher complications of pancreatitis and cholangitis in the stent group (45%) than in the balloon dilatation group (7%)159

Fully covered self-expandable metal stents are now well established in the management of benign biliary strictures of different aetiologies.160 161 Case series including small numbers of patients with PSC also suggest a role for these stents in dominant strictures below the liver hilum due to PSC.161–163

Some strictures are not amenable to, or do not require, endoscopic intervention. In these patients, careful consideration should be made about a conservative, radiological or surgical (including liver transplantation) approach to treatment before ERCP is performed. If ERCP is performed in the presence of dominant stricture, it is important that consideration is made of possible CCA and that appropriate sampling is undertaken if there is any clinical suspicion of malignancy.

Recommendation 11: We recommend that non-invasive investigations such as MRCP, dynamic liver MRI and/or contrast CT should be performed in patients who have new or changing symptoms or evolving abnormalities in laboratory investigations (strength of recommendation: STRONG; quality of evidence: MODERATE).

Recommendation 12: We recommend that patients with PSC should ordinarily not undergo ERCP until there has been expert multidisciplinary assessment to justify endoscopic intervention (strength of recommendation: STRONG; quality of evidence: MODERATE).

Recommendation 13: We recommend that in patients undergoing ERCP for dominant strictures, pathological sampling of suspicious strictures is mandatory (strength of recommendation: STRONG; quality of evidence: STRONG).

Recommendation 14: We recommend that in patients undergoing ERCP for dominant strictures, biliary dilatation is preferred to the insertion of biliary stents (strength of recommendation: STRONG; quality of evidence: MODERATE).

Cholangitis

Cholangitis is a common complication of PSC. Bacterobilia is reported in 55% of patients at the time of liver transplantation, increasing to at least 77% in those who have predisposing factors such as biliary strictures or previous biliary instrumentation.182 Cholangitis can present without significant change in baseline liver biochemistry as infections can be limited to small liver segments. A clear risk factor for cholangitis or positive bile cultures is previous ERCP with or without therapeutic intervention, with the highest risk seen when stents are left in situ. A study (not in PSC) reported a positive bile culture rate of 98% in those with a stent in situ and 55% in those without.183 The number and variety of bacterial isolates were inversely proportional to the time since the last ERCP.182 Another potential source of cholangitis is portal bacteraemia, which has been described in patients with active colitis.184 ERCP is a risk major factor for cholangitis in PSC and antibiotics should be routinely used as recommended above.

Biliary infections are often polymicrobial, but the most common organisms are Eschericia coli, Klebsiella, Enterococcus, Clostridium, Steptococcus, Pseudomonas and Bacteroides species.185 The choice of antibiotic agent should be directed by local practice after taking into consideration the history, severity of liver or renal disease and bacterial sensitivities. A common first-line agent for mild episodes is a fluoroquinolone such as ciprofloxacin. More severe cases are usually treated with intravenous cephalosporins or extended spectrum penicillins with the addition of anaerobic cover.185 186 Candida species have been isolated from the bile of 8/67 (12%) patients with PSC undergoing ERCP.187 However, the clinical relevance of fungal contamination of bile is unknown. Antifungal therapy should be considered in those with cholangitis not responding to antibiotic therapy.

Patients with severe acute cholangitis and dominant bile duct strictures require urgent biliary decompression, as the mortality in those untreated is high.186 In patients with recurrent cholangitis secondary to complex intrahepatic cholangiopathy, rotation of antibiotics is occasionally used. This can lead to multiple antibiotic resistances and should be avoided where possible. Where this option is considered, expert multidisciplinary assessment, including formal microbiology advice, should be sought.

Cirrhosis, portal hypertension and liver failure

In an observational series of 174 patients with PSC who underwent a liver biopsy, advanced fibrosis or cirrhosis was found in 43% of patients with asymptomatic disease, and in 69% of those who were symptomatic64; 25% died of liver failure. Other studies have shown similar results.15 188 It is likely that these series are subject to referral bias with patients at a more advanced stage than many patients routinely followed up in local centres, but they indicate a high prevalence of advanced parenchymal liver disease in PSC. The true prevalence of portal hypertension is not known, but extrapolating data from clinical findings, such as the presence of splenomegaly and oesophageal varices, suggests that clinically significant portal hypertension is present in 30%.15 188

Metabolic bone disease

As with other cholestatic liver diseases, osteopenia and osteoporosis are common in PSC.189 190 In a study of 237 patients who underwent annual measurement of bone mineral density, 15% had evidence of osteoporosis, equating to a 24-fold risk of osteoporosis compared with an age-matched population.191 In this study, the presence of older age (>54 years), low body mass index (<24 kg/m²) and presence of IBD were strong risk factors of low bone density (prevalence of 75% with all three risk factors and 3% with none), but interestingly, cumulative dose of corticosteroids was not. Patients may also have coexistent vitamin D deficiency, but overt osteomalacia is uncommon. UK guidelines on the management of osteoporosis associated with chronic liver disease advise that all patients should receive lifestyle advice and those with cirrhosis or advanced cholestasis should have bone densitometry performed every 2 years.192 In practice, young patients with early disease are at low risk of low bone density and will not usually require formal testing. Patients with a high risk of bone disease and those requiring steroid treatment for IBD or liver transplantation should be treated with daily vitamin D 400 IU (10 μg) and calcium supplements if calculated dietary calcium intake is insufficient. Those with confirmed osteoporosis should be treated according to BSG and NICE guidelines and fracture risk scores (http://www.nice.org.uk).192

Recommendation 19: We recommend that all patients with PSC should have a risk assessment for osteoporosis. Once osteoporosis is detected, treatment and follow-up should be in accordance with national guidelines (strength of recommendation: STRONG; quality of evidence: MODERATE).

Poor nutrition and fat soluble vitamin deficiency

Poor nutrition is common in chronic liver disease and should be considered and treated appropriately in patients with PSC. Advanced cholestasis can result in malabsorption of fat-soluble vitamins. In advanced disease before transplantation, deficiency of vitamin A, D and E in 82%, 57% and 43%, respectively, are reported, but much lower levels of deficiency are seen earlier in the disease process.193 Evidence of deficiency of any measurable vitamin should lead to consideration of empirical replacement with multivitamins.

Recommendation 20: Poor nutrition and fat-soluble vitamin deficiency are relatively common in advanced PSC and we suggest that clinicians should have a low threshold for empirical replacement (strength of recommendation: WEAK; quality of evidence: MODERATE).

Fatigue and depression

Fatigue is a common symptom of patients with chronic liver disease, but no treatments have been proved to be beneficial.194 Depression is also common in people with chronic illnesses, and there are mixed reports of the association between depression and fatigue in PSC.194 195 One study directly assessing quality of life and fatigue scores in PSC, reported a lower incidence of fatigue than in the general population and when present, symptoms were associated with depression rather than severity of liver disease.194 There does not appear to be a role for the treatment of fatigue using antidepressants without clear symptoms of depression.196–198

Recommendation 21: We recommend that in patients with fatigue, alternative causes should be actively sought and treated (strength of recommendation: STRONG; quality of evidence: LOW).

Pruritus

Pruritus has a significant detrimental effect on quality of life for patients with PSC.199 The mechanism of pruritus in cholestasis remains unclear, which makes targeted treatment difficult. Antihistamines are not effective for the pruritus of cholestasis. There are few data for treatment in PSC and most recommendations are extrapolated from trials in PBC.200 Pruritus associated with advanced disease is difficult to treat medically, and treatable biliary obstructions should be sought and relieved as above. The first line of medical treatment is usually cholestyramine, colesevelam or colestipol. Care is needed to avoid administering soon before or after other medications. Further possible treatments include rifampicin and opiate antagonists such as naltrexone. The efficacy of these drugs is variable and they tend to have significant side effects. Patients with intractable pruritus not responsive to standard medical treatment should be offered referral to a specialist and/or transplant unit for further management.

Recommendation 22: We suggest that cholestyramine (or similar) is first-line medical treatment for pruritus. Rifampicin and naltrexone are second-line therapies (strength of recommendation: WEAK; quality of evidence: LOW).

Cancer

Cholangiocarcinoma (CCA)

Malignancy, particularly CCA, is now the the most common cause of death in patients with PSC who have not undergone transplantation.201 The incidence of CCA in PSC is between 0.6% and 1.5% a year, with a prevalence of 6–13% and a lifetime risk of up to 20%.15 62 64 125 188 202 203 Approximately half of cases of PSC-associated CCA are identified within a year of presentation of PSC, and may be the reason for presentation of previously unrecognised PSC.125 203–205 There is no clear evidence that the risk of developing cancer is related to the duration of PSC disease. The incidence of CCA is highest in those with dominant strictures, with up to 76% located within the perihilar region.125 CCA is rare in small duct PSC.75 76 203 206 A summary for management of suspected cholangiocarcinoma is outlined in figure 2.

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Figure 2

Algorithm for the investigation of possible cholangiocarcinoma in patients with primary sclerosing cholangitis.

The usual modes of presentation are with upper abdominal pain, worsening liver biochemistry, jaundice and a raised serum CA19.9. CCA tends to spread by local invasion of the bile ducts and much less often with mass formation, so that cross-sectional imaging may fail to identify the tumour. It is difficult to distinguish benign from malignant biliary strictures by MRCP or ERCP. Endoscopic assessment of suspicious biliary strictures is discussed above. Physicians should refer patients to units with experience in ERCP and EUS if there is continuing concern about biliary malignancy in patients with PSC.

Tumour markers used in clinical practice are CA19.9 and CEA but neither is sufficiently sensitive or specific for the diagnosis of CCA either alone or in combination.207–210 These studies used primarily CA19.9 with a cut-off point of 37–186 kU/L. The sensitivity and specificity ranged between 50% and 89% and 54% and 98%, respectively. The positive predictive value is low. The main problem with this marker is that it is frequently elevated in cholestasis and cholangitis, both of which are common in PSC. Another finding was that those with high levels of CA19.9 had unresectable disease, suggesting that it is not useful in surveillance.211 The utility of CA19.9 and various imaging modalities was reported in a large series of patients with PSC; no level of CA19.9 demonstrated reliable detection of CCA.212 Early retrospective data suggest that a rising trend in CA19.9 for individual patients may be more predictive than the actual level for the presence of early cholangiocarcinoma.213 Therefore, CA19.9 may be useful for supportive evidence of CCA but is not reliable for screening or for confirmation of the diagnosis of CCA.

Early reports suggested positron emission tomography (PET) scanning may be useful for surveillance or investigation of suspected CCA.214 However, a further study of 36 patients (without PSC) with suspected CCA demonstrated a sensitivity of 85% for mass-forming tumours, 65% for metastases but only 18% for infiltrating tumours.215 One small prospective study on the use of PET in transplant assessment (n=10, four with CCA) reported a sensitivity of 75% and false-positive rates of 20% in the presence of cholangitis.216 Studies of PET scanning in sporadic CCA, demonstrate sensitivities of 61–92% and specificities of 75–93%.215 217 The detection rate falls to as low as 36–59% in cases of extrahepatic disease with infiltrating rather than mass-forming disease.218 219 Therefore, PET is not routinely recommended for surveillance or diagnosis of CCA in PSC.

Cases of suspected CCA should be referred for review in the regional specialist hepatobiliary and pancreatic MDM or liver transplant centre. Decisions on treatment depend on the stage of disease. Chemotherapy remains the main palliative treatment for patients with CCA and will be directed by the specialist MDM. Although resectional surgery may be curative, this is usually not possible in patients with PSC (particularly with hilar/intrahepatic malignancy) because of either advanced stage malignancy at diagnosis, complex biliary structuring or coexistent parenchymal liver disease precluding a major liver resection. A retrospective multicentre study of 47 patients with liver transplantation for hilar CCA (not PSC specific) reported a high rate of recurrence (34%) and poor 5-year survival (22%).220 A Canadian study of patients who received a transplant for PSC reported an 80% recurrence rate, and a median time to recurrence of 26 months in 10 patients with an incidental finding of CCA in the explant.221 UK data demonstrate similar outcomes.222

In the UK, CCA remains a contraindication to liver transplantation after poor outcomes, with high rates of recurrence reported, even in cases of incidental CCA found in liver explants.171 However, in selected cases, 3-year survival rates of 35–50% have been achieved.223 A series from the USA suggests that highly selected cases with early-stage hilar CCA have good outcomes when treated with preoperative chemotherapy and radiotherapy followed by transplantation.224 225 A more recent review of 287 patients in 12 US centres undergoing neoadjuvant chemo-radiotherapy followed by transplantation for early CCA reported a 65% 5-year recurrence-free survival.226 Decisions about transplantation when biliary dysplasia is identified at tissue sampling are complex and require in-depth discussions in a formal liver transplant MDM.

Recommendation 23: We suggest that an elevated CA19.9 may support a diagnosis of suspected cholangiocarcinoma but has a low diagnostic accuracy. Routine measurement of serum CA19.9 is not recommended for surveillance for cholangiocarcinoma in PSC (strength of recommendation: WEAK; quality of evidence: MODERATE).

Recommendation 24: We recommend that when a diagnosis of cholangiocarcinoma is clinically suspected, referral for specialist MDM review is essential (strength of recommendation: STRONG; quality of evidence: MODERATE).

Recommendation 25: We recommend that where cholangiocarcinoma is suspected, contrast-enhanced, cross-sectional imaging remains the initial preferred investigation for diagnosis and staging (strength of recommendation: STRONG; quality of evidence: HIGH). Confirmatory diagnosis relies on histology with the approach to tissue sampling guided by MDM review. Options include ERCP-guided biliary brush cytology/FISH/ endobiliary biopsy/cholangioscopy/EUS-guided biopsy and/or percutaneous biopsy (strength of recommendation: STRONG; quality of evidence: HIGH).

Other hepatopancreaticobiliary cancers

Gallbladder polyps are more often malignant in patients with PSC than in those without PSC, and malignancy may occur even in polyps <1 cm.227 228 A study of explanted livers from patients with PSC reported a high prevalence of dysplasia or cancer of the gallbladder, with 14% of resected gallbladders having foci of adenocarcinoma.229 No studies have been carried out examining prospective ultrasound surveillance of gallbladder polyps in patients with PSC. The US guidelines recommend cholecystectomy when polyps are identified, but this should be balanced against the increased risk of surgery in patients with more advanced cirrhosis and portal hypertension.

Early reports suggested that hepatocellular carcinoma (HCC) has a prevalence of 2–4% in PSC.62 230 However, other reports suggest that the incidence of HCC in patients with PSC is extremely low, even in the presence of cirrhosis.231 Pancreatic cancer is reported to have a 14-fold standard incidence ratio compared with expected rates in the general population.62

Recommendation 26: We suggest that an annual ultrasound scan of the gallbladder should be performed in patients with PSC. If polyps are identified, treatment should be directed by specialist HPB MDM (strength of recommendation: WEAK; quality of evidence: LOW).

Future studies

Research into PSC has been mostly through small case series and uncontrolled trials in specialist units. Most centres will have an insufficient number of patients to affect their clinical service, for audit purposes or to undertake independent clinical trials. A recent consensus on endpoints for future studies was reported by an international PSC working group.243

Studies in progress include investigations into the role of norUDCA, farnesoid X receptor agonists, bile salt transporter protein inhibitors, antibiotics and monoclonal antibody blockade of receptors thought to be activated in the pathogenesis of PSC.244

Gastroenterology units should be encouraged to link patient databases in order to improve knowledge of the natural history of PSC and response to treatments, and to improve future clinical trials. These efforts should be coordinated by UK-PSC, BSG and/or the British Association for the Study of the Liver (BASL) and the National Institute for Health Research (NIHR) rare diseases initiative. Studies should include a prospective national repository of clinical samples. Future clinical trials should be registered with the NIHR.

Research and clinical audit questions that may require more clarity include:

1. What constitutes a diagnosis of PSC in UK practice?

2. How should patients with unexplained abnormal liver biochemistry and IBD be evaluated, labelled and diagnosed, particularly when MRCP is normal?

3. How can we improve stratification for risk of (a) liver disease, (b) disease progression and (c) cancer?

4. What is the optimal timing and type of intervention for patients with dominant strictures?

5. Are there any other existing and/or new drugs which may be useful in the medical management of PSC?

6. Can we develop a robust database to map the epidemiology, progression and management of PSC in the UK as well as to assess causes of death?

7. What is the optimal approach to surgical management in patients with PSC requiring colectomy and/or liver transplantation?

8. Can we report patient perceptions of problems and risks of living with PSC with the aim of improving wellbeing for patients and carers.

Background

Treatment

There are few randomised placebo-controlled data to guide treatment of IgG4-SC (or IgG4-RD in general), but large case series have reported rapid and favourable disease control after an initial course of steroids. A common steroid regimen used in the UK is oral prednisolone 40 mg daily for 2–4 weeks, subsequently reduced by 5 mg every week over approximately 8–12 weeks. The effect is measured by clinical response (eg, resolution of jaundice, liver biochemistry, etc) and radiological findings such as resolution of mass lesions and improvement in cholangiopathy. Lack of objective improvement in radiological abnormalities on repeat imaging at weeks 4–8 suggests either an incorrect diagnosis or a fibrotic, non-inflammatory phase of disease. Although serum IgG4 often falls in response to steroids, its level is not used to monitor or plan further treatment. Relapse after cessation of steroid treatment may occur in at least 60% of patients with IgG4-SC, and is more common in those with multiorgan involvement. To date, practice in Europe and North America has often been to introduce an immunomodulator (eg, azathioprine, mercaptopurine or mycophenolate) with further steroids if there is evidence of relapse,266 272 or a high risk of relapse. There is no clear consensus on dosing regimens, including the need to maintain low dose steroids in those receiving azathioprine (usually at a dose of 2 mg/kg/day). Japanese experts favour maintenance steroid treatment, and a recent randomised study (in IgG4-RD, rather than specifically IgG4-SC) showed lower rates of relapse at 3 years in those treated with maintenance prednisolone 5–7.5 mg (23%) than in those given an initial steroid withdrawal regimen (58%).273 Emerging evidence from case series suggest that >95% of these patients with IgG4-RD will respond to biological therapy using anti-CD20 monoclonal antibodies such as rituximab.272 Rituximab is likely to be the preferred treatment for patients who fail to respond to first- or second-line treatment or whose disease flares on withdrawal of steroids, particularly in those with multisystem or complex disease. Small studies have suggested the efficacy of rituximab in patients with IgG4-SC.274 275 Given the complexity of management it is advisable for patients with possible IgG4-SC to be referred to specialists or centres with experience of the disease to establish the diagnosis, plan management and recruit into trials.

Recommendation 5: We recommend that patients with active IgG4–SC should be given corticosteroids as first-line treatment (strength of recommendation: STRONG; quality of evidence: MODERATE).

Recommendation 6: We recommend that all patients with IgG4-SC, including those with multiorgan involvement in IgG4-RD, should be considered for continued immunosuppressive therapy (strength of recommendation: STRONG; quality of evidence: MODERATE).

Recommendation 7: We recommend that patients with complex IgG4-SC and those with suspected malignancy should be referred to a specialist MDM for review (strength of recommendation: STRONG; quality of evidence: LOW).

Audits and future studies

Research in the field of IgG4-SC/IgG4-RD has increased significantly over the past 10 years, initially in small case series and uncontrolled trials in specialist units. Most centres will have an insufficient number of patients to affect their clinical service, for audit purposes or to undertake independent clinical trials. Gastroenterology units should be encouraged to link patient databases in order to improve knowledge of the natural history and response to treatments, and to improve future clinical trials.

Research and clinical audit topics that may require more clarity include:

1. The aetiopathogenesis of IgG4-RD.

2. Development of a robust database to map the epidemiology, progression and management of IgG4-RD in the UK and to assess causes of death.

3. The optimal medical management for patients with IgG4-SC.

4. Reporting of patient perceptions of problems and risks of living with IgG4-RD.